“Trombosi ed Emostasi in Ostetricia e Ginecologia”
Varese, 22 settembre 2012
Aula Magna-Dipartimento di Biologia-Università degli Studi dell’Insubria-Via Dunant, 3-Varese-
Prevenzione del TEV in Chirurgia
Ginecologica:
Eparine a basso peso molecolare
Luigi Steidl
Centro Trombosi ed Emostasi
U.O. di Medicina Interna I
Ospedale di Circolo
Varese
Il rischio peri-operatorio standard
Pre-operatorio
Intra-operatorio
Post-operatorio
Rischio
emorragico
--
+++*
- +*
Rischio
trombotico
--
+++*
+++*
*Secondo la procedura chirurgica
Prevenzione del TEV in Chirurgia Ginecologica:
Eparine a basso peso molecolare
Premessa
Dimensioni del problema
Metodi di tromboprofilassi
farmacologica e non farmacologica
Stratificazione del rischio trombotico ed
emorragico
Tempi e dosi
Linee Guida
Prevenzione del TEV in Chirurgia
Ginecologica
• Dati estrapolati e derivati da studi in pazienti
di chirurgia generale e addomino-pelvica
• Mancanza di dati recenti specifici in
ginecologia
• Bilancio tra benefici (riduzione dell’incidenza
di TEV) e costi in termini di eventi emorragici
Horlander KT , et al. Arch Intern Med. 2003; 163 (14): 1711-1717
Geerts WH, Bergqvist D, Pineo GH, et al., Chest 2008;133: 381-453
Incidenza di tromboembolismo
venoso nei pazienti ricoverati
Pazienti internistici
Chirurgia generale
Chirurgia ginecologica
Chirurgia urologica
Neurochirurgia
Chirurgia ortopedica maggiore
Traumi maggiori
Terapia intensiva
Trauma spinale
10-20%
15-40%
15-40%
15-40%
15-40%
40-60%
40-80%
10-80%
50-100%
National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism in inpatients undergoing
surgery. NICE clinical guideline No. 46:1–160. Available at: http://www.nice.org.uk/CG046. Accessed March 31, 2008
Levels of Thromboembolism Risk and Recommended
Thromboprophylaxis in Hospital Patients
Lassen MR, Borris LC, Backs S, et al. Blood Coagul Fibrinolysis 1999; 10(suppl 2):S45–S51
Prevention of Venous Thromboembolism
The Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy
Chest 2004;126:338S-400S
Risk factors for VTE
 Surgery

Trauma (major or lower extremity)

Immobility, paresis

Malignancy

Cancer therapy (hormonal, chemotherapy, or radiotherapy)

Previous VTE

Increasing age

Central venous catheterization

Pregnancy and the postpartum period

Estrogen-containing oral contraception or hormone replacement therapy

Selective estrogen receptor modulators

Acute medical illness
Rationale for Thromboprophylaxis in
Hospitalized Patients
W. H. Geerts et al., CHEST 2004; 126:338S–400S
Prevenzione del TEV in Chirurgia
Calze elastiche
Compressione pneumatica intermittente
Eparina non frazionata a basse dosi
EBPM a dosi profilattiche
Fondaparinux
Ac. Acetilsalicilico
Filtri cavali
Sorveglianza periodica con c-US
Advantages and Limitations of
Mechanical
Thromboprophylaxis Modalities
Advantages
• Do not increase the risk of
bleeding
• Can be used in patients at high
bleeding risk
• Efficacy has been demonstrated in
a number of patient groups
• May enhance the effectiveness of
anticoagulant thromboprophylaxis
• May reduce leg swelling
Limitations
•
•
•
•
•
•
•
•
•
•
•
Not as intensively studied as pharmacologic
thromboprophylaxis (fewer studies and smaller)
No established standards for size, pressure, or
physiologic features
Many specific mechanical devices have never
been assessed in any clinical trial
Almost all mechanical thromboprophylaxis trials
were unblinded and therefore have a potential for
bias
In high-risk groups are less effective than
anticoagulant thromboprophylaxis
Greater effect in reducing calf DVT than proximal
DVT
Effect on PE and death unknown
May reduce or delay the use of more effective
anticoagulant thromboprophylaxis
Compliance by patients and staff often poor
Trials may overestimate the protection compared
with routine use
Cost: associated with purchase, storage,
dispensing, and cleaning of the devices, as well
as ensuring optimal compliance
A brief history of anticoagulant therapy
Unfractionated heparins: antithrombin (AT)-dependent
inhibition of Factor Xa and IIa in a 1:1 ratio
Parenteral
Vitamin K antagonists: indirectly affect
synthesis of multiple coagulation factors
Oral
Parenteral
1940s
Low molecular weight heparin:
AT-dependent inhibition of Factor Xa >IIa
Parenteral
Direct Factor IIa inhibitors
Parenteral
Indirect Factor Xa inhibitors
1930s
1980s
1990s
2000s
Direct Factor IIa
inhibitors
Oral Direct Factor Xa
inhibitors
Oral
Alban, Eur J Clin Invest 2005
Link, Circulation 1959
REGIMENS TO PREVENT VENOUS
THROMBOEMBOLISM
Surgical conditions
LMWH
Enoxaparin 40 mg sc once daily
Nadroparin 2850-3400 U sc once daily
Dalteparin 2500-5000 U sc once daily
Danaparoid 750 U sc q12h
LDUH
Heparin 5000 U sc q8-12h
Nicolaides et al, Int Angiol, 1997
Risk Stratification in General, Abdominal-Pelvic,
Gynecologic Surgery
Risk of VTE
procedure-specific factors
low-risk procedures
laparoscopic surgery, appendectomy, transurethral
prostatectomy, inguinal herniorrhaphy, unilateral or
bilateral mastectomy
high-risk procedures
Open-abdominal and open-pelvic procedures
Cancer surgery
patient-specific factors
age, prior VTE, cancer, anesthesia >2 h, bed rest >4
days, male sex, sepsis, pregnancy or postpartum state,
central venous access
Andtbacka RH , et al. Ann Surg . 2006 ; 243 ( 1 ): 96 – 101
Clarke-Pearson DL, et al.Obstet Gynecol . 2003 ; 101 ( 1 ): 157 - 163
Caprini Risk Assessment Model (modified)
VTE risk categorization:
•very low (0-1 point)
•low (2 points)
•moderate (3-4 points)
•high (≥5 points)
Caprini JA . Dis Mon . 2005 ; 51 ( 2-3 ): 70 – 78
Caprini JA, Arcelus JI, Hasty JH, Tamhane AC, Fabrega F. Semin Thromb Hemost . 1991
Rogers Risk Assessment Model
VTE risk categorization:
•low (< 7 points)
•moderate (7-10 points)
•high (> 10 points)
Rogers SO Jr , Kilaru RK , Hosokawa P , Henderson WG , Zinner MJ , Khuri SF. J Am Coll Surg. 2007; 204 (6): 1211-1221
Risk Assessment Models (RAM)
Limiti:
• Mancanza di validazione clinica
• Time-consuming
Baseline Risk and Risk Factors for Major
Bleeding Complications
•
Meta-analysis of seven randomized trials of LMWH in absence of
prophylaxis:
– major bleeding in the control groups: 1.2%
(95% CI, 0.9%-1.7%)
Mismetti P, et al. Br J Surg . 2001 ; 88 ( 7 ): 913 - 930
•
Meta-analysis of thirty-three randomized trials of LMWH in absence of
prophylaxis:
– major bleeding in the control groups:Leonardi
0.7% MJ,
(95%
CI, 0.92%-1.57%)
et al. Arch Surg . 2006 ; 141 ( 8 ): 790 - 797.
•
Bleeding risk with LMWH:
– Major bleeding (RR, 2.03; 95% CI, 1.37-3.01)
– Wound hematoma (RR, 1.88; 95% CI, 1.54-2.28)
Sweetland S, et al. Million Women Study Collaborators. BMJ . 2009 ; 339
DVT After Laparoscopic Procedures
Higher VTE Risk in Cancer
Surgery Patients
 Increased age
 Longer immobilisation (pre and post
operatively)
 Associated treatment with
 Radiotherapy
 Chemotherapy
 Central venous catheters
 Longer operative procedures
 Traumatic and extensive surgery
Bergqvist D. Thromb Res 2001; 102:V209-13.
The risk of postoperative DVT is increased
after general surgery for cancer
Cancer patients
Non-cancer patients
Kakkar et al. 1970
24/59 (41%)
38/144 (26%)
Hills et al. 1972
8/16 (50%)
7/34 (21%)
Walsh et al. 1974
16/45 (35%)
22/217 (10%)
Rosenberg et al. 1975
28/66 (42%)
29/128 (23%)
Sue-Ling et al. 1986
12/23 (52%)
16/62 (26%)
Allan et al. 1983
31/100 (31%)
21/100 (21%)
9/37 (22%)
13/53 (24%)
Multicenter Trial 1984
All
128/346 (37%)
146/738 (20%)
Prandoni P et al. Haematologica 1999;84:437-45
Outcomes in Cancer Patients
Undergoing Surgery*
Meta-analysis of all randomised studies comparing LMWH and UFH in
patients undergoing general surgery (18 – 46,000 patients)
Outcome
Cancer surgery
DVT
Non-Cancer surgery
6%
4.8%
Clinical PE
0.8%
0.4%
Clinical VTE
1.8%
1.2%
Death
4.8%
1.5%
Major haemorrhage
8.1%
2.7%
* Patients all receiving unfractionated
heparin
Mismetti P, et al. Br J Surg 2001; 88: 913-30.
Rischio di TEV
Incidenza di TEV nel tempo
?
Tempo
Chirurgia
Dimissione
Standard duration of thromboprophylaxis
after general surgery
In thromboprophylaxis studies
in general and abdominal-pelvic surgery
7-10 days
Geerts WH et al. Chest 2004;126;338S-400S
Standard duration of thromboprophylaxis
after general surgery
In thromboprophylaxis studies
in general and abdominal-pelvic surgery
-oncology setting-
4 weeks
Bergqvist D, Agnelli G, Cohen AT, et al. N Engl J Med 2002; 346:975–980
International guidelines
Nessuna grande variazione rispetto a
edizioni precedenti (2001-2004-2008)
Scomparsa del capitolo specifico sulla
Chirurgia ginecologica ricompreso
nella chirurgia generale
Prevention of VTE in Non-orthopedic Surgical Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS,
9TH ED: ACCP GUIDELINES
Chest 2012;141:227S-277S
3.6.1. For general and abdominal-pelvic surgery patients at very low risk
for VTE (<0.5%; Rogers score, <7; Caprini score, 0), we recommend
that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C)
prophylaxis be used other than early ambulation.
3.6.2. For general and abdominal-pelvic surgery patients at low risk for
VTE ( 1.5%; Rogers score, 7-10; Caprini score, 1-2), we suggest
mechanical prophylaxis, preferably with IPC, over no prophylaxis (Grade
2C) .
3.6.3. For general and abdominal-pelvic surgery patients at moderate risk
for VTE (3.0%; Rogers score, >10; Caprini score, 3-4) who are not at high
risk for major bleeding complications, we suggest LMWH (Grade 2B),
LDUH (Grade 2B), or mechanical prophylaxis, preferably with IPC (Grade
2C), over no prophylaxis.
Prevention of VTE in Non-orthopedic Surgical Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS,
9TH ED: ACCP GUIDELINES
Chest 2012;141:227S-277S
3.6.4. For general and abdominal-pelvic surgery patients at moderate risk
for VTE (3.0%; Rogers score, >10; Caprini score, 3-4) who are at high
risk for major bleeding complications or those in whom the
consequences of bleeding are thought to be particularly severe, we
suggest mechanical prophylaxis, preferably with IPC, over no
prophylaxis (Grade 2C) .
3.6.5. For general and abdominal-pelvic surgery patients at high risk for
VTE (6.0%; Caprini score, ≥5) who are not at high risk for major bleeding
complications, we recommend pharmacologic prophylaxis with LMWH
(Grade 1B) or LDUH (Grade 1B) over no prophylaxis. We suggest that
mechanical prophylaxis with ES or IPC should be added to
pharmacologic prophylaxis (Grade 2C) .
Prevention of VTE in Non-orthopedic Surgical Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS,
9TH ED: ACCP GUIDELINES
Chest 2012;141:227S-277S
3.6.6. For high-VTE-risk patients undergoing abdominal or pelvic surgery
for cancer who are not otherwise at high risk for major bleeding
complications, we recommend extended-duration pharmacologic
prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis
(Grade 1B) .
3.6.7. For high-VTE-risk general and abdominal-pelvic surgery patients
who are at high risk for major bleeding complications or those in whom the
consequences of bleeding are thought to be particularly severe, we
suggest use of mechanical prophylaxis, preferably with IPC, over no
prophylaxis until the risk of bleeding diminishes and pharmacologic
prophylaxis may be initiated (Grade 2C) .
Prevention of VTE in Non-orthopedic Surgical Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF
THROMBOSIS, 9TH ED: ACCP GUIDELINES
Chest 2012;141:227S-277S
Rischio
trombotico
Rischio
Durata
emorragico
Profilassi
farmacologica
Profilassi non
farmacologica
Molto basso
Nessuna(1B)
Nessuna (2C)
Basso
Nessuna(1B)
CPI (2C) o CE
Moderato
Basso
EBPM o ENF BD (2B)
CPI (2C)
Moderato
Alto
Nessuna
CPI (2C)
Alto
Basso
EBPM o ENF BD (1B)
+ CE o CPI (2C)
Alto
(+neoplasia)
Basso
Alto
Alto
4 settimane
EBPM (1B)
Nessuna
CPI: compressione pneumatica intermittente; CE: calze elastiche;
EBPM: eparine a basso PM; ENF BD: eparina non frazionata a basso dosaggio
CPI (2C)  sino a rischio
emorragico basso
Prevention of Venous Thromboembolism
American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition)
CHEST 2008; 133:381S–453S
2.3.1. For low-risk gynecologic surgery patients who are
undergoing minor procedures and have no additional risk
factors, we recommend against the use of specific
thromboprophylaxis other than early and frequent
ambulation (Grade 1A).
2.3.2. For gynecology patients undergoing entirely
laparoscopic procedures, we recommend against routine
thromboprophylaxis, other than early and frequent
ambulation (Grade 1B).
2.3.3. For gynecology patients undergoing entirely
laparoscopic procedures in whom additional VTE risk
factors are present, we recommend the use of
thromboprophylaxis with one or more of LMWH, LDUH,
IPC, or GCS (Grade 1C).
Prevention of VTE in Non-orthopedic Surgical Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF
THROMBOSIS, 9TH ED: ACCP GUIDELINES
Chest 2012;141:227S-277S
3.6.8. For general and abdominal-pelvic surgery patients at high risk for
VTE (6%; Caprini score, ≥5) in whom both LMWH and unfractionated
heparin are contraindicated or unavailable and who are not at high risk
for major bleeding complications, we suggest low-dose aspirin (Grade
2C) , fondaparinux (Grade 2C) , or mechanical prophylaxis, preferably
with IPC (Grade 2C) , over no prophylaxis
3.6.9. For general and abdominal-pelvic surgery patients, we suggest that
an IVC filter should not be used for primary VTE prevention (Grade 2C) .
3.6.10. For general and abdominal-pelvic surgery patients, we suggest
that periodic surveillance with VCU should not be performed (Grade 2C) .
All women who have had an emergency caesarean
section (category 1–3) should be considered for
thromboprophylaxis with LMWH for 7 days after
delivery.
All women who have had an elective caesarean
section (category 4) who have one or more additional
risk factors (such as age over 35 years, BMI greater
than 30) should be considered for
thromboprophylaxis with LMWH for 7 days after
delivery.
Prevention of VTE in Non-orthopedic Surgical Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS,
9TH ED: ACCP GUIDELINES
Chest 2012;141:227S-277S
6.2.1. For women undergoing cesarean section without additional
thrombosis risk factors, we recommend against the use of thrombosis
prophylaxis other than early mobilization (Grade 1B).
6.2.2. For women at increased risk of VTE after cesarean section because
of the presence of one major or at least two minor risk factors, we suggest
pharmacologic thromboprophylaxis (prophylactic LMWH) or mechanical
prophylaxis (elastic stockings or intermittent pneumatic compression) in
those with contraindications to anticoagulants while in hospital following
delivery rather than no prophylaxis (Grade 2B).
6.2.3. For women undergoing cesarean section who are considered to be
at very high risk for VTE and who have multiple additional risk factors for
thromboembolism that persist in the puerperium, we suggest that
prophylactic LMWH be combined with elastic stockings and/or intermittent
pneumatic compression over LMWH alone (Grade 2C) .
Conclusioni
(take home messages)
Nessuna grande novità nel panorama
recente
Indicazioni personalizzate sulle RAM
Rischio di sanguinamento
Efficacia e sicurezza delle EBPM
Non ancora studiati i Nuovi
Anticoagulanti Orali (NAO)
Contraccezione ormonale e HRT e rischio
tromboembolico
Take-home messages [1]
La COC e’ un fattore di rischio per TEV?
Si (OR:  5)
E la contraccezione per altra via di somministrazione?
Si (≠IUD medicato, impianto sc, progestinico iniettabile)
Se si, è un fattore di rischio minore o maggiore?
Minore (20-40aa=baseline: 1/10000COC: 3-6/10000)
E’ utile lo screening trombofilico a tutte le donne?
No, solo “famiglie trombofiliche”
E’ anche un fattore di rischio cardiocerebrovascolare?
Si (OR:  2)
E la terapia ormonale sostitutiva?
Si (OR:  3,5)
Esami di Trombofilia Venosa
Anticorpi
Antitrombina
antifosfolipidi (ACA +
Proteina C ed S
antiB2GPI) + LAC
della
(aPTT + DVVRT)
coagulazione
FII mutazione
G20210A
FV Leiden
Omocisteina
Eseguire la determinazione prima
della somministrazione di contraccettivi !!
FVIIIC
Approccio razionale alla prescrizione della contraccezione
ormonale: Take-home messages [1]
1- Tipo del contraccettivo ed entità del rischio :
L’estradiolo è la componente di un COC che impatta maggiormente sul rischio di TEV.
Il rischio di TEV è strettamente correlato e direttamente proporzionale alla dose di EtinilEstradiolo.
I diversi progestinici modificano l’effetto protrombotico degli estrogeni.
2- I progestinici di III generazione hanno un RR doppio di TEV rispetto a quelli di II
Generazione.
3- Non ci sono chiare evidenze sul minor rischio di TEV di COCs con estrogeni
naturali e/o COC somministrati per vie alternative (ring-cerotto), benchè senz’altro i
suddetti COCs abbiano un migliore profilo metabolico.
4- Screening trombofilie mirato e non su larga scala!
La gravidanza puo’ già in donne sane e senza fattori di rischio aggiuntivi, essere
considerata uno stress test sul sistema coagulatorio e una storia ostetrica negativa
per TEV in queste donne puo’ essere un’indicazione sufficiente alla prescrizione di
OC.
5- Controindicazione alla prescrizione di COC nelle pazienti con pregresso TEV!
Take-home messages [2]
Consigli pratici prima della prescrizione della COCs:
•
•
Accurata anamnesi personale & familiare 2008 Consensus Conference SNLG
“Prevenzione delle complicanze trombotiche
Misurazione PA
•
Non si raccomanda né prima di prescrivere un contraccettivo
né durante l’uso l’esecuzione routinaria di :
-Esami ematochimici generici
-Test generici di coagulazione
-Test specifici per trombofilia
•
Partire con CO a basso dosaggio (20-30 γ) + progestinico di II
generazione
•
Attenzione a fumo ed obesità!!
associate all’uso di E/P nell’età riproduttiva
Tutto il resto non è indispensabile.